Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations

Abstract

Importance: Previous studies have shown lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations.

Objective: To study the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD) and to investigate the association of known HDL-C genotypes with high HDL-C level outcomes.

Design, setting, and participants: This prospective, multicenter, cohort study, conducted from 2006 to present in the UK and from 2003 to present in Atlanta, Georgia, recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. Patients without confirmed CAD were excluded from the study. Data analyses were conducted from May 10, 2020, to April 28, 2021.

Exposure: High HDL-C levels (>80 mg/dL).

Main outcomes and measures: The primary outcome was all-cause death. The secondary outcome was cardiovascular death.

Results: A total of 14 478 participants (mean [SD] age, 62.1 [5.8] years; 11 034 men [76.2%]) from the UKB and 5467 participants (mean [SD] age, 63.8 [12.3] years; 3632 men [66.4%]) from the EmCAB were included in the study. Over a median follow-up of 8.9 (IQR, 8.0-9.7) years in the UKB and 6.7 (IQR, 4.0-10.8) years in the EmCAB, a U-shaped association with outcomes was observed with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (>80 mg/dL) were associated with increased risk of all-cause death (hazard ratio [HR], 1.96; 95% CI, 1.42-2.71; P < .001) and cardiovascular death (HR, 1.71; 95% CI, 1.09-2.68; P = .02) compared with those with HDL-C levels in the range of 40 to 60 mg/dL in the UKB after adjustment for confounding factors. These results were replicated in the EmCAB. These associations persisted after adjustment for the HDL-C genetic risk score within the UKB. Sensitivity analyses demonstrated that the risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB (HR, 2.63; 95% CI, 1.75-3.95; P < .001 vs HR, 1.39; 95% CI, 0.82-2.35; P = .23).

Conclusions and relevance: Results of this cohort study suggest that very high HDL-C levels are paradoxically associated with higher mortality risk in individuals with CAD. This association was independent of the common polymorphisms associated with high HDL-C levels.

Figure 1.. Nonlinear Association Between High-Density Lipoprotein (HDL) Cholesterol Levels and Adverse Outcomes

UK Biobank (UKB) coronary artery disease cohort model of all-cause death (A) and cardiovascular death (C) adjusted for age, sex, race and ethnicity, body mass index, hypertension, diabetes, smoking, triglycerides, low-density lipoprotein (LDL) cholesterol, stroke history, heart attack history, estimated glomerular filtration rate (eGFR), and frequent alcohol use (defined as alcohol consumption ≥3 times per week). Emory Cardiovascular Biobank (EmCAB) model of all-cause death (B) and cardiovascular death (D) adjusted for age, sex, race and ethnicity, body mass index, hypertension, diabetes, current/former smoking, triglycerides, LDL cholesterol, heart failure history, myocardial infarction history, eGFR, frequent alcohol use (defined as ≥8 alcohol beverages per week), statin use, aspirin use, β-blocker use, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use. HR indicates hazard ratio.

Figure 2.. Forest Plot of High-Density Lipoprotein (HDL) Cholesterol (>80 mg/dL) Compared With Reference HDL Cholesterol (40-60 mg/dL)

UK Biobank (UKB) coronary artery disease cohort model of all-cause death (A) and cardiovascular death (C) adjusted for age, sex, race and ethnicity, body mass index, hypertension, diabetes, smoking, triglycerides, low-density lipoprotein (LDL) cholesterol, stroke history, heart attack history, estimated glomerular filtration rate (eGFR), and frequent alcohol use (defined as alcohol consumption ≥3 times per week), excluding the variable of stratification. Emory Cardiovascular Biobank (EmCAB) model of all-cause death (B) and cardiovascular death (D) adjusted for age, sex, race and ethnicity, body mass index, hypertension, diabetes, current/former smoking, triglycerides, LDL cholesterol, heart failure history, myocardial infarction history, eGFR, frequent alcohol use (defined as ≥8 alcohol beverages per week), statin use, aspirin use, β-blocker use, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, excluding the variable of stratification. P values indicate test for interaction between HDL cholesterol greater than 80 mg/dL group and variable of stratification. HR indicates hazard ratio. ^aP value < .05.